The present invention relates to bioabsorbable fused implants which are effective in administering hormones subcutaneously in mammals over a protracted time period, and to the method of manufacturing the fused implants.
Steroids are currently used for treating a variety of conditions in mammals, including cancer, endocrine and gynecological problems and the control of fertility.
A variety of methods and apparatus have been known as aids in controlling fertility in mammals, including humans. Some approaches of current interest are condoms, IUCD's, diaphrams, spermidical creams, jellies and foams, and tablets and pills containing various steroids to be administered orallyl. Many of these approaches to fertility control are not completely effective and some cause undesirable side effects as a result of administering sex hormones such as estrogen and progesterone, normally associated with pregnancy, to non-pregnant females. These side effects range from migraine headaches, vomiting, fatigue, nausea, and hypertension to a higher risk of heart attacks.
The administration of steroid sex hormones such as 19-norprogesterone derivatives is known to prevent luteinization, that is, the production of the corpus luteum, as well as preventing ovulation, that is, the release of an egg from the ovary. The anti-luteinizing and anti-ovulation effects of these hormones have been used for several years to induce reversible protracted sterility in mammals, including humans. Pincus, G., Chang, M. C. et al. Endocrinol. 59, 694 (1956) Rock, J., Garcia, C. R. et al. Amer. J. Obst. and Gynecol. 79, 758 (1960).
One of the experimental methods of administering steroid sex hormones has been through subcutaneous implants. See, for example, U.S. Pat. No. 3,800,038 to Rudel; Kincl, Acta Endocrinologica 64 (1970) 253-264 and Kochakian, American J. Physiol., 145 549 (1945). The implantation of pellets under the skin is a well-established method of administering steroids and other compositions. In 1936, M. J. Shear, American Journal of Cancer, 26:322-332 (1936), reported the use of fused implants of cholesterol and a carcinogen to induce tumors in animals. P. M. Bishop, in Lancet, Aug. 11, 1951, pp. 229-232, in an article entitled "Absorption of Hormone Implants in Man" summarizes the use of implants and reports that in 1938 he recorded the effects of implanting a 14 mg. pellet of oestrone in an ovariectomised woman; in 1939, Salmon et al. treated menopausal women with oestrodiol-benzoate implants; Thorn and Firor in 1940 treated Addison's disease by implanting pellets of deoxycortone and found that their effect lasted 9 to 12 months; in 1943, Greenblatt studied the effect of androgen implants in women with functional menstrual disorders; in 1947, Zondek suggested the introduction of pellets deep in the vaginal mucosa to avoid undesirable general systemic effects from hormone treatment; and, in 1949, Vargas treated diabetics by the implantation of pellets of protamine-zinc insulin and cholesterol.
The implants used in these early experiments were made according to a method developed by, among others, Shear, supra; Organon Laboratories Ltd., England, and M. B. Shimkin and J. White, Endocrinology, 29:1020-25 (1941). According to this method, the proximal end of a Pyrex glass tube of a desired length and bore is fitted with a rubber cap and a tightly fitting steel wire is inserted into the tube through the rubber cap to act as a plunger. In order to prevent adhering of the implants to the walls, the glass is lightly oiled with liquid petrolatum. The desired quantity of the active chemical and other ingredients are mixed and melted in an oil bath. The resulting solution is drawn up into the lubricated glass tube by means of the wire plunger. As soon as the material solidifies in the tube, it is extruded by the plunger. The solid rod thus formed is divided into implants of desired size by means of a razor blade. The implants are then washed in ether and again in alcohol to remove the oil on the surface and to smooth the rough edges.
The implants are introduced into the subcutaneous tissue of the subject by means of a trocar fitted with a plunger. The implants fit into the trocar, and no preparatory skin incision is necessary.
The glass tubing method of making fused implants has several major disadvantages. The fused implants tend to adhere to the glass wall and the glass must be lubricated to allow for removal of the implants. The use of lubrication is a serious drawback in preparing implants for human use. Implants for use in humans must be highly purified, and the use of oils and petrolatum on the glass tubing wall introduces an unwanted and troublesome impurity which must be scrupulously removed before the implant is suitable for human use.
The glass tubing method of the prior art has additional problems when used specifically for producing steroid implants such as are used for fertility control. According to this method, the steroid mixture is melted in a system that is open to the atmosphere. Since in most steroid mixtures melting occurs at a temperature above 100.degree. C., there is danger of thermal decomposition of the hormone. The presence of oxygen from the atmosphere quickly activates undesirable oxidation changes in the steroid. In addition, if the mixture is heated above 500.degree. C., the Pyrex glass begins to soften and may impart further impurities to the molten steroid mixture.
The problem of thermal decomposition of the components of an implant must also be considered during sterilization. Sterilization is often accomplished by heating the object to 100.degree. C. for 60 minutes. The glass tube method of manufacturing implants is carried out open to the atmosphere and heating the components of the implant in contact with the oxygen in the atmosphere causes further decomposition products which seriously impair the purity of the implant.
A further disadvantage of the glass-tubing method is that it generally produces a cylindrical implant. Studies have shown that an implant of ellipsoidal shape in cross section is preferred for many reasons. Since glass is rigid and non-pliable, it is difficult to form glass tubing in an elliptical shape. The inability to easily produce an ellipsoidal implant is a serious drawback of the glass tubing system.
In the past, the use of the fused implants as a means of administering medication, especially sex hormones, has met with the problem of controlling the release of the drug to obtain constant long-term release of the therapeutic agent. In some pellet compositions, the dissolution rate was too slow and not enough of the therapeutic compound was released to the patient's system or, on the contrary, the dissolution rate was too rapid, which resulted in overdosing and insufficient length of drug release. It has been reported by M. B. Shimkin and J. White, Endocrinology, supra, and others that by combining cholesterol with the active ingredients in the pellet a long-acting implant can be produced. It was observed by Kochakian supra that compressed cholesterol-hormone implants were absorbed more slowly and uniformly than pure pellets, and in 1961 A. Lipschutz and R. Iglesias, Nature, 190 p. 174 (1961), found that implants containing 20% 19-norprogesterone and 80% cholesterol induced protracted sterility in mice.
Several other researchers, including Kincl supra and Rudel in U.S. Pat. No. 3,800,038, have prepared fused hormone-cholesterol implants for use in preventing conception but they have had serious disadvantages. Kincl reported that the desired rate of release of an active ingredient in an implant could be obtained by manipulating the concentration of the compound, the dimension of the implant and the nature of the carrier phase but he reports that he was unable to obtain reproducable results and Kincl suggested that the problem might be due to the manner in which the mixtures were made. Kincl employed the glass tubing method of forming implants.
Rudel's process also used the glass tube method of making implants, but in addition, Rudel's fused pellets are formed from a eutectic mixture at low temperatures which further adds to the problems of manufacturing the pellets. The eutectic point is that point in melting two different crystal substances at which the crystal substances have the lowest possible melting point which is lower than the melting point of either of the pure compounds. The mixture which crystalizes at that point is called the eutectic mixture or the eutectic. The eutectic of a two component system such as Rudel used has a fine grain structure and is a mixture of two solid phases.
R. S. Smart, in a paper entitled "Liquid Crystalline Behaviour in Mixtures of Cholesterol with Steroid Hormone" Nature, 215 (1967) pp. 957-958, reports on the composition and characteristics of steroid hormone mixtures similar to those used by Rudel. Smart found that steroids in cholesterol mixtures caused anisotropic melts which gave rise to eutectics which in most cases had a composition of 1:1 steroid to hormone that is 50% steroid and 50% hormone.
Other than the data reported by Smart, the phase diagrams needed to establish the eutectic point are not available for mixtures of cholesterol and steroids. Since the transition phases and phase diagrams of the common synthetic protestins have not been reported, it is difficult to define and select compositions which will give a eutectic melt.
A further disadvantage of the fused implants reported by Kincl and Rudel is in their composition. Kincl's implants contained from 98-70% cholesterol and 2-30% progestational hormone and Rudel's implants contain from 40-75% cholesterol and from 60-25% hormone. Since both the Rudel and Kincl implants contain a high percentage of cholesterol and a relatively small amount of the steroid, the implants would have to be impractically large in order to supply an effective daily dose of the hormone. For example, 80-100 micrograms norethindrone per day are necessary to control fertility in human females. In order to provide this daily dose over a prolonged period of time, for example, 6 months, an implant composed of the Rudel and Kincl type cholesterol-steroid mixture would be too large for practical purposes.
It has now been found that a fused ellipsoidal shaped pharmaceutical implant comprising a solid dispersion of an effective amount of a steroid uniformly dispersed in a matrix of a suitable lipoid carrier such that the ratio of the steroid to the carrier is 99:1 to 80:20, respectively, provides an effective long-term implant for subcutaneous administration in mammals.
The present invention is directed to a novel fused implant which eliminates the problems and disadvantages of earlier fused steroid-lipid implants and to a method of implant manufacture.
Specifically, the fused implants of the present invention are a bioabsorbable fused pharmaceutical implant, preferably ellipsoidal in cross section, for subcutaneous administration in mammals designed to slowly release a constant and effective amount of a steroid over a prolonged period comprising a solid dispersion of an effective amount of a steroid uniformly dispersed in a matrix of a suitable lipoid carrier, such that the weight ratio of the steroid to the lipoid carrier being in the approximate range of 99:1 to 80:20, respectively.
The preferred size range of the implant is 4-8 mm in length and 2.4 mm in minimum diameter and 2.8 mm in maximum diameter. The preferred weight range of the implant is 24 mg-48 mg.
It has also been found that the implant of the present invention can be prepared by heating a mixture of pure steroid and a meltable lipoid carrier at a temperature above the melting point of the steroid and the lipoid carrier in an inert atmosphere.
Specifically, the implants of the present invention are manufactured by a process which comprises the steps of purifying the steroid, storing the purified steroid under an inert atmosphere preferably nitrogen, loading a mixture of the pure steroid and the pure lipoid carrier into a thin walled tube of suitable length and diameter made from a flexible inert plastic having a non-stick surface, preferably a fluorocarbon resin such as Teflon.sup.1, compacting the ingredients in the tube, heating the tube at a temperature above the melting point of the steroid and the lipoid carrier to fuse the mixture, and allowing the tube to cool, each step being carried out in an inert atmosphere preferably nitrogen and under aseptic conditions. FNT .sup.1 Teflon is a trademark for polytetrafluorethylene registered by Du Pont.
In a preferred embodiment of the invention, a single implant is made. Sufficient steroid and carrier to prepare one implant are loaded under an inert atmosphere into a piece of fluorocarbon resin tubing approximately 10 cm in length, 2.4 mm in minimum diameter and 2.8 mm in maximum diameter, compacted and then heated on an aluminum block, preheated to a temperature above the melting point of the steroid. The tubing is then allowed to cool. This procedure yields a single fused ellipsoidal implant which can be removed from the tubing and stored under inert aseptic conditions or stored directly in the tubing under inert aseptic conditions.
In an alternative embodiment, multiple implants of random size are prepared. 1-2 grams of a suitable steroid and carrier are loaded under an inert atmosphere into a U-shaped piece of ellipsoidal fluorocarbon resin tubing approximately 25-27" in length, evacuated and flushed with an inert gas such as nitrogen. The U-shaped tube is heated in an oil bath, preheated above the melting point of the steroid, for 2 minutes. On cooling, multiple pellets of various sizes are formed and can be removed under aseptic conditions, graded and cut to desired lengths or they can be stored directly in the tubing under inert aseptic conditions.
The fused implants of the present invention may contain a steroid selected from the group consistion of: 17.alpha.-hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, melengestrol acetate, anagestone acetate, medrogestone, droxone, quingestrone, proligestone, chlormadinone acetate, chlorsuperlutin, .DELTA.-chlormadinone acetate, cyproterone acetate, chlometherone, haloprogesterone, fluorgestone, clogestone, gestaclone, gestonorone caproate, methynodiol acetate, oxogestone, amidinone, R-5020, dimethisterone, ethisterone, allylestrenol, ethynerone, ethynodiol diacetate, lynestrenol, norethisterone, norethisterone acetate, norethisterone oenanthate, norethynodrel, norgestrienone, norvinodrel, quingestanol acetate, retroprogesterone, dydrogesterone, trengestone, 4-azidonorethisterone, cingestol, R-2323, d-norgestrel, norethindrone, norethindrone acetate, ethynydiol diacetate, norethandrolone, ethinyloestradiol, mestranol, quinestrol, estrofurate, esrazinol hydrobromide, estramustine phosphate, BDH 10131, sodium oestrone sulphate, piperazine oestrone sulphate, oestrone, equilenin, equilin, oestriol, quinestradol, epimestrol, oestriol succinate, stilboestrol, fosfestrol, dienoestrol, hexoestrol, benzoestrol, promestrol dipropionate, chlorotrianisene, methallenestril, clomiphene citrate, cyclofenil, MER-25, ICI-46,474, P 1496, testosterone, analogues of testosterone, cortisone and analogues of cortisone. The chemical structures for some of these compounds can be found in Sex Hormone Pharmacology, J. Brotherton, 1976, pp. 5-8.
The fused implant of the present invention also contains a lipoid carrier selected from the group consisting of: Cholesterol and its organic carboxylic esters containing from 1-20 carbon atoms.
The preferred implant of this invention contains a synthetic contraceptive progestin selected from the group consisting of d-norgestrel (NG), norethindrone (NET) and norethindrone acetate (NETA), with cholesterol as the lipoid carrier.
The steroids and lipoid carriers of the present invention are bioabsorbable, that is, can be totally absorbed by the host's body. Because of this feature, the implants of the present invention need not be removed from the host once it is implanted, since it is eventually totally absorbed by the host's body, and thus eliminates the need for surgical removal of the implant.
The method of manufacture using fluorocarbon resin tubing has several advantages, one of which is that it is flexible and implants with ellipsoidal cross sectioned design can be readily manufactured. Thin walled fluorocarbon tubing is preferred and it can be made ellipsoidal by pressing against the tubing wall with a stick or other suitable instrument.
Although the size of the needle required for insertion of the implant is governed by the size of the largest diameter of the ellipsoidal implant, the overall stretching of the skin is reduced by using an ellipsoidal shaped implant. The slightly flat elliptical shape of the implant reduces bulging when the implant is placed under the skin while retaining approximately the same surface area as a cylindrical implant. An implant in the form of an ellipsoidal cylinder of dimensions of, for example, 5 mm in length, lies flat under the skin in the subcutaneous fatty tissue layer creating a better physical-morphological condition for absorption. The rounded edges of an ellipsoidal implant prevents it from bulging under the skin and thereby creates less irritation and foreign body tissue reaction under the skin following implantation. On the other hand, the cylindrical pellet formed from the glass tube method lacks these benefits and as such, the glass tube method is a less desirable method of preparing fused implants for human implantation.
The ellipsoidal cross sectional design is the preferred form for the novel implant since it provides a more constant release of the active ingredient from the implant than an implant uniformly circular in cross section. The fact that a disc or slab shaped device will give more constant release than a cylinder shaped device is discussed in Controlled Release Polymeric Formulations, edited by D. R. Paul and F. W. Harris, ACS Symposium Series 33, American Chemical Society, Washington, D.C. 1976; Emmens, C. W., Endocrinology 28:633, 1941, pp. 633-642 and Shimkin, M. B. et al., Endocrinology, Vol. 35, 1944, pp. 283-295.
The primary feature governing the release from the implant is the surface area. The relationship is expressed by the Noyes-Whitney equations: EQU da/dt=KS (C.sub.s -c),
where
a=the amount of drug dissolved in time t,
K=solution rate constant of the drug,
S=surface area of the solid pellet,
C.sub.s =concentration of the drug in the diffusion layer surrounding the pellet
c=concentration of the drug in the dissolution medium.
A further advantage of the fused implants prepared by the method of the present invention is that, with proper precautions, they are sterile when made and can be directly inserted into the host without further treatment. When the implants are manufactured by a fusion method in fluorocarbon resin tubing at a temperature 5.degree.-10.degree. C. above the melting point of the highest individual component, the implants are sterile both on the surface and in the interior.
The fusion method of the present invention has many other advantages over the prior art glass tubing method. Unlike the prior art methods, the fusion in fluorocarbon resin tubing is carried out in an inert atmosphere, such as nitrogen, which enables the high temperature fusion reaction to proceed without oxidation of either the steroid or lipoid carrier. This feature allows for the production of a pure fused implant with no reaction impurities.
The fusion method of the present invention is also superior to the glass tubing method of fusion, in that once fused and solidified, the implants do not adhere to the side of the non-stick tubing and can be easily removed without the aid of oils or pretroleum jelly lubricants which are needed in the glass tubing method. This is a particularly important advantage when the implants are to be used for human implants since any traces of a foreign substance would cause serious problems when the implant is inserted subcutaneously. The implants can be removed by inserting a sterile plunger into the tubing or the tubing can be easily split using a razor blade or other knife-like objects for the easy removal of the implants under aseptic conditions.
A further advantage of using the fluorocarbon resin system is that these resins are inert under the conditions of the process and there is no interaction between the tubing walls and the organic compounds even at the high fusion temperatures. Since the fluorocarbon resin tubing is inert, flexible and unbreakable, the fused implants need not be removed from the tubing once they are formed but rather the tubing can be used as a convenient means of storing the fused implants under nitrogen.
In addition, when the system is used to manufacture a single implant, the fluorocarbon resin tubing can serve as part of a built-in trocar system for injecting the implant into the body. The fluorocarbon, polytetrafluoroethylene, such as Teflon, is particularly suited for this application since Teflon is used extensively for heart valve repair and replacements in humans, as well as in arterial and veinous replacements and it is known to be nontoxic and highly suited for insertion into the body.